Mycoses involve skin diseases typified by various trichophytoses, leprid, psoriasis, cutaneous candidiasis, and the like, and deep mycoses typified by mycotic meningitis, mycotic respiratory infection, hematomycosis, mycosis of urinary tract, and the like.
Among these, deep mycoses cannot be treated by using a usual antibiotic or chemotherapeutic agent, and thus the number of patients suffering therefrom shows a tendency to rise. Accordingly, there have been required drugs efficacious in treating them.
At present, only four drugs are clinically usable in treating deep mycoses, namely, amphotericin B which is a peptide antibiotic, flucytosine which is a growth inhibitor for fungal cells, and fluconazole and itraconazole which are azole antifungal agents. However, these agents are not satisfactory yet. Moreover, it is said that deep mycoses would frequently cause multiple fungal infection. Thus, it has been required to develop a drug having a broader antifungal spectrum. Under these circumstances, a triazole derivative, (R)-(-)-3-methyl-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluor omethyl)phenyl]butan-2-ol, and pharmaceutically acceptable salts thereof have been found (JP-A-3-223266 and JP-A-7-2802). This compound will be sometimes referred to as "the present compound" in this description.
The present compound has excellent characteristics of: (1) showing an antifungal effect on the genus Aspergillus in addition to the genera Candida and Cryptococcus; (2) showing an antifungal effect even on the genus Candida which is fluconazole-resistant; (3) showing an excellent therapeutic effect on a neutropenia systemic fungal infection model (in vivo); (4) causing a more remarkable decrease in the viable count in the lung in a local infection model (in vivo) than existing drugs; (5) having a higher selectivity of P450 derived from fungi and animals than existing drugs; (6) having a water solubility which is usable as injections; and (7) having a safety margin comparable to existing drugs. Thus, it is expected that it is useful as a remedy for deep mycoses.
The present compound has a water solubility which is usable as injections. Therefore, it is preferred that the present compound is used as injections from the viewpoint of providing dosage forms over a wide range, in particular, those for intravenous administration.
Although the antifungal effect of the present compound was proved by orally administering it to mice in JP-A-3-223226, it is disclosed that the compound can be formulated by conventional methods into antifungal agents in various dosage forms, such as tablets, granules, powders, capsules, suspensions, injections, suppositories, external preparations, and the like. When injections are prepared, it is also disclosed that the present compound may be preliminarily dissolved, dispersed, emulsified, etc. in an aqueous carrier, such as distilled water for injection or the like, or formulated into powders for injection which are to be dissolved when they are used, namely, the present compound is usable as injections by conventional methods.
In order to prepare an injection for intravenous administration, it is necessary to add an isotonizing agent (an osmotic regulator) to regulate the osmotic pressure of the aqueous solution. Thus, the present inventors prepared an injection by using sodium chloride (0.9 W/V %) commonly used as an isotonizing agent. As a result, they have found that the present compound is decomposed at a considerably high ratio by heat sterilization and that its decomposition product is increased when stored over a long time. To develop an injection, it is necessary to minimize the decomposition during heating and enhance the stability. However, no such injection has been obtained so far.